Worldwide, approximately 3 million die each year from tobacco-related disease. Many smokers are unable or unwilling to quit. As a consequence, consideration has been given to reduction of tobacco toxin exposure as a complement to prevention and treatment to reduce the health burdens associated with tobacco use. Basic questions related to assessing the feasibility of potential reduced exposure products and methods remain unanswered. The specific aims of this TTURC continue to be to comprehensively examine various aspects of tobacco harm reduction: 1) effective methods to reduce tobacco toxin exposure and disease risk; 2) biomarkers to assess this reduction; 3) mechanisms associated with reductions in tobacco toxin exposure; 4) individual differences that moderate exposure and disease risk; and 5) the role of this approach in the treatment of smokers. Project l, Lung carcinogen biomarkers in long-term tobacco users, will examine the predictive validity ofbiomarkers, some of which are used in Project 3, for lung cancer. Project 2, Nicotine exposure in rats, will focus on developing animal models and interventions for nicotine exposure reduction and compensation. Project 3, Methods for exposure reduction in humans, paralleling methods described in Project 2, will examine mechanisms, moderators and outcomes of various exposure reduction strategies. Project 4, Longitudinal care: smoking reduction to aid cessation, will determine if a longitudinal care intervention that includes a reduced tobacco exposure treatment approach, compared to a discrete care model, will improve tobacco abstinence. Three cores- the Administration, Communications, and Theory Core, the Biomarkers Core and the Design and Analysis Core will provide critical support for these projects. Mechanisms to ensure a transdisciplinary approach to science include: 1) a multidiscipliuary team of investigators with expertise ranging from organic chemistry to behavioral sciences to epidemiology, 2) a shared conceptual model or framework which integrates models for harm reduction with tobacco treatment; 3) shared methodologies; 4) mechanisms for communication and translation; 5) pilot projects to expand the scope of the center and engage additional scientists; and 6) a training program to mentor pre- and post-doctoral students, and junior faculty. The results of research from this TTURC will provide the scientific basis for urgent policy, public education, and regulatory efforts to reduce tobacco harm.